Research in the Cell Biology Section, Neurogenetics Branch focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including mitochondrial disorders, dystonia, and the hereditary spastic paraplegias (HSPs). These disorders, which together afflict millions of Americans, worsen insidiously over a number of years, and treatment options are limited for many of them. Our laboratory is investigating inherited forms of these disorders, using molecular and cell biology approaches to study how mutations in disease genes ultimately result in cellular dysfunction. Over the past several years, we have studied the interplay of the proteins that are mutated in SPG11 and SPG15, the two most common autosomal recessive HSPs. These proteins interact with one another as well as with a new adaptor protein complex -- AP5, one component of which, AP5Z1, is mutated in SPG48. Importantly, we have identified a fundamental role for the SPG15 and SPG11 proteins in lysosomal biogenesis and autophagic lysosomal reformation. Studies in these areas were published in the Journal of Clinical Investigation in 2014. Studies of the SPG48 protein AP5Z1 were published in Human Molecular Genetics in 2015 and Neurology: Genetics in 2016. In 2018, we published a study in Human Molecular Genetics, in collaboration with Dr. Xue-Jun Li, investigating patient derived induced pluripotent stem cells for SPG15 and SPG48; we found abnormalities in mitochondrial structure and function within axons. Lastly, we are investigating the functions of the SPG8 protein strumpellin, which is part of the WASH protein complex implicated in the shaping of endosomes through alterations of the actin cytoskeleton; we published a mechanistic study of the SPG8 protein in Nature Communications in early 2016 and another study is in revision at Science Signaling. Taken together, we expect that our studies will advance our understanding of the molecular pathogenesis of the HSPs. Such an understanding at the molecular and cellular levels will hopefully lead to novel treatments to prevent the progression of these disorders.